The invention relates to a novel process for preparing optically active trimethyllactic acid and/or esters thereof by catalytic hydrogenation of trimethylpyruvic acid and/or esters thereof.
Optically active trimethyllactic acid or its esters are required, for example, as building blocks for HIV protease inhibitors (Bioorg. Med. Chem. Lett., 1995, 5, 1729-1734). Its synthesis is therefore of particular importance.
A number of synthesis routes are already known. Biotechnol. Biotech., 1986, 8-13, describes, for example, enzymatically reducing trimethylpyruvic acid in an enantioselective manner using an alcohol dehydrogenase. However, the process has the disadvantage that the reaction must be carried out in the presence of a cofactor whose regeneration is complex and expensive.
In addition, both chemical (Bull. Chem,. Soc. Jpn., 1968, 41, 2178-2179) and biological methods are described (Appl. Environ. Microbio., 1983, 45, 884-891) for the racemate resolution of trimethyllactic acid. The disadvantage of these methods is that the maximum yield for the target enantiomer, as is customary in racemate resolutions, is 50%, and the unwanted enantiomer must usually be discarded.
A further method is the diazotization of tert-leucine with subsequent hydrolysis of the diazonium compound with water (Chem. Ber., 1991, 124, 849-859). However, this process requires the very expensive enantiomerically pure tert-leucine and, due to unwanted rearrangement reactions, leads to by-products and is therefore uneconomic.
J. Org. Chem., 1988, 53, 1231-1238 and J. Org. Chem., 1986, 51, 3396-3398 disclose the preparation of enantiomerically pure trimethyllactic esters by reducing trimethylpyruvic esters with chirally modified borane reagents. However, this process has the disadvantage that stoichiometric amounts of the borane reagent, which is expensive and complicated to synthesize, are required.
EP-A 901,997 discloses a process for preparing optically active alcohols by asymmetric hydrogenation of ketones. However, the process is restricted exclusively to aliphatic or aliphatic/aromatic ketones, hydrogenation being carried out in the presence of transition metal complex catalysts, a base, and a diamine. The transition metal complex catalysts contain bisphosphine ligands.
EP-A 643,065 discloses further specific bisphosphines which can be used for asymmetric hydrogenations in the form of their complexes with metals of Group VIII, in particular ruthenium. Suitable substrates mentioned are generally substituted or unsubstituted xcex1- or xcex2-keto esters, xcex1- or xcex2-keto amides, xcex1- or xcex2-amino- or xcex1- or xcex2-hydroxyketones and acetamidocinnamic acid derivatives. The focus of use is the asymmetric hydrogenation of 2-arylpropenoic acids.
In addition, EP-A 654,406 describes ferrocenyldiphosphines as ligands for homogeneous rhodium and iridium catalysts, which are used for the asymmetric hydrogenation of prochiral compounds containing carbon-carbon and carbon-heteroatom double bonds. Examples of such compounds are prochiral olefins, enamines, imines, and ketones.
For the sterically demanding methyl phenylpyruvate, Tetrahedron: Asymmetry, 5, 675-690 describes an asymmetric hydrogenation in the presence of various phosphine ligands which, although they predominantly lead to very high yields, at the same time give only unsatisfactory enantiomeric excesses, some of which are in the range of only 27 or 30% ee.
The object of the present invention is thus to provide a novel process which makes possible the enantioselective preparation of optically active trimethyllactic acid and its esters with high yields and does not require the use of expensive reagents.
The invention relates to a process for preparing optically active trimethyllactic acid and/or esters thereof of formula (I) 
wherein R1 represents hydrogen, alkyl, aryl, aralkyl, or heterocyclyl, comprising enatiomerically hydrogenating trimethylpyruvic acid and/or its esters of formula (II) 
wherein R1 has the meanings specified for formula (I), in the presence of a catalyst comprising one or more noble metal complexes containing optically active bisphosphines as ligands.
The inventive process makes possible the enantiomerically pure preparation of trimethyllactic acid and/or its esters of the general formula (I), where the radical R1 represents H, alkyl, aryl, aralkyl, or heterocyclyl. The alkyl radicals in the above-mentioned substituents can in each case be unbranched or branched.
Preferably, the radical R1 represents H, C1-C20-alkyl, C6-C14-aryl, C7-C15-aralkyl, or C2-C12-heterocyclyl. Suitable C2-C12-heterocyclyl groups can have one or more three- to- seven-membered rings having at least one ring nitrogen, oxygen, and/or sulfur heteroatom in addition to the specified number of ring carbon atoms and are preferably C2-C12-heteroaryl groups in which at least one of the rings is aromatic. Particularly preferably, R1 represents H, C1-C10-alkyl, C6-C10-aryl, C7-C11-aralkyl or C2-C9-heteroaryl and, in particular hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, neopentyl, isopentyl, phenyl, benzyl, naphthyl, 2-furyl, 3-furyl, 2-pyrrolyl, and 3-pyrrolyl.
The alkyl, aryl, aralkyl, and heteroaryl radicals can, in addition, also be further substituted by Cl, Br, F, I, C1-C4-alkoxy, or C1-C4-alkyl.
In the inventive process, catalysts having the following enantiomerically pure bisphosphines of the general formula (B1) to (B15) can be used, for example:
(1) a bisphosphine of the general formula (B1) 
where
R2 denotes phenyl, 3-methylphenyl, 4-methylphenyl, 3,5-dimethylphenyl, 4-methoxyphenyl, 3,5-dimethyl-4-methoxyphenyl, cyclohexyl, or cyclopentyl, or
(2) a bisphosphine of the general formula (B2) 
where
R3 denotes phenyl, 4-methylphenyl, 3,5-dimethylphenyl, 4-methoxyphenyl, 3,5-dimethyl-4-methoxyphenyl, or cyclohexyl, or
(3) a bisphosphine of the general formula (B3) 
where
R3 denotes phenyl, 4-methylphenyl, 3,5-dimethylphenyl, 4-methoxyphenyl, 3,5-dimethyl-4-methoxyphenyl, or cyclohexyl,
R4 denotes H, methyl, or methoxy,
R5 denotes H, methyl, methoxy, or chlorine, and
R6 denotes methyl, methoxy, or trifluoromethyl, or
(4) a bisphosphine of the general formula (B4) 
where
R7 represents methyl, ethyl, propyl, or isopropyl, or
(5) 2,3-bis(diphenylphosphino)butane of the formula (B5) 
(6) 1,2-bis(diphenylphosphino)propane of the formula (B6) 
(7) 5,6-bis(diphenylphosphino)-2-norbornane of the formula (B7) 
(8) 1-substituted 3,4-bis(diphenylphosphino)pyrrolidine of the formula (B8) 
(9) 2,4-bis(diphenylphosphino)pentane of the formula (B9) 
(10) 2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)-butane of the formula (B10) 
(11) 1,2-bis-[(o-methoxyphenyl)phenylphosphino]ethane of the formula (B11) 
(12) 1-[1xe2x80x2,2-bis(diphenylphosphino)ferrocenyl]ethanol of the formula (B12) 
(13) 1-tert-butoxycarbonyl-4-diphenylphosphino-2-diphenylphosphino-methyl-pyrrolidine of the formula (B13) 
(14) a bisphosphine of the general formula (B14) 
where
R8 denotes phenyl, cyclohexyl, 4-methylphenyl, 4-methoxyphenyl, 3,5-dimethylphenyl, 3,5-dimethyl-4-methoxyphenyl, 4-tert-butyl, or 3,5-di-tert-butyl, or
(15) a ferrocenyldiphosphine of the general formula (B15) 
where
R8 has the meaning specified for formula (B14) and
R9 denotes C1-C8-alkyl, phenyl, or phenyl monosubstituted to trisubstituted by C1-C4-alkoxy.
Suitable bisphosphines of the above-mentioned formula (B1) are.
2,2xcexc-bis(diphenylphosphino)-1,1xcexc-binaphthyl,
2,2xcexc-bis(di-4-tolylphosphino)-1,1xcexc-binaphthyl
described in J. Org. Chem., 1986, 51, 629.
Suitable bisphosphines of the above-mentioned formula (B3) are
(5,5xe2x80x2-dichloro-6,6xe2x80x2-dimethoxybiphenyl-2,2xe2x80x2-diyl)-bisdiphenylphosphine
described in EP-A 749,973
(4,4xe2x80x2,6,6xe2x80x2-tetramethyl-5,5xe2x80x2-dimethoxybiphenyl-2,2xe2x80x2-diyl)-bis(diphenylphosphine)
(4,4xe2x80x2,6,6xe2x80x2-tetramethyl-5,5xe2x80x2-dimethoxybiphenyl-2,2xe2x80x2-diyl)-bis(di-p-methoxyphenylphosphine)
described in Chem. Pharm. Bull., 1991, 39, 1085
(4,4xe2x80x2,6,6xe2x80x2-tetratrifluoromethylbiphenyl-2,2xe2x80x2-diyl)-bis(diphenylphosphine)
(4,6-ditrifluoromethyl-4xe2x80x2,6xe2x80x2-dimethyl-5xe2x80x2-methoxybiphenyl-2,2xe2x80x2-diyl)-bis(diphenyl-phosphine)
described in Synlett 1991, 827
(2-dicyclohexyl-2xe2x80x2-diphenylphosphino-4,4xe2x80x2,6,6xe2x80x2-tetramethyl-5,5xe2x80x2-dimethoxybiphenyl-2,2xe2x80x2-diyl)-bis(diphenylphosphine)
described in Tetrahedron: Asymmetry, 1992, 3, 13
(6,6xe2x80x2-dimethyl-2,2xe2x80x2-biphenylene)-bis(diphenylphosphine)
(4,4xe2x80x2,6,6xe2x80x2-tetramethyl-2,2xe2x80x2-biphenylene)-bis(diphenylphosphine)
(3,3xe2x80x2,6,6xe2x80x2-tetramethyl-2,2xe2x80x2-biphenylene)-bis(diphenylphosphine)
(4,4xe2x80x2-difluoro-6,6xe2x80x2-dimethyl-2,2xe2x80x2-biphenylene)-bis(diphenylphosphine)
(4,4xe2x80x2-bis(dimethylamino)-6,6xe2x80x2-dimethyl-2,2xe2x80x2-biphenylene)-bis(diphenyl-phosphine)
(6,6xe2x80x2-dimethyl-2,2xe2x80x2-biphenylene)-bis(di-p-tolylphosphine)
(6,6xe2x80x2-dimethyl-2,2xe2x80x2-biphenylene)-bis (di-o-tolylphosphine)
(6,6xe2x80x2-dimethyl-2,2xe2x80x2-biphenylene)-bis(di-m-fluorophenylphosphine)
1,11-bis(diphenylphosphino)-5,7-dihydrodibenzo[c,e]oxepine
described in JP-B 4-15796 (where xe2x80x9cBxe2x80x9d denotes: examined Japanese patent application)
(6,6xe2x80x2-dimethoxybiphenyl-2,2xe2x80x2-diyl)-bis(diphenylphosphine)
(5,5xe2x80x2,6,6xe2x80x2-tetramethoxybiphenyl-2,2xe2x80x2-diyl)-bis(diphenylphosphine)
(6,6xe2x80x2-dimethoxybiphenyl-2,2xe2x80x2-diyl)-bis(di-p-tolylphosphine) and
(4,4xe2x80x2,5,5xe2x80x2,6,6xe2x80x2-hexamethoxybiphenyl-2,2xe2x80x2-diyl)-bis(diphenylphosphine)
described in JP-A 3-5492.
Suitable bisphosphines of the formula (B4) are:
1,2-bis(2,5-dimethylphosphorano)benzene
1,2-bis(2,5-diethylphosphorano)benzene
1,2-bis(2,5-dipropylphosphorano)benzene and
1,2-bis(2,5-diisopropylphosphorano)benzene
described in J. Am. Chem. Soc., 1993, 115, 10125.
Preferred noble metal complex catalysts in the inventive process are particularly those based on ruthenium, rhodium, and iridium. Particularly preferably, ruthenium complex catalysts are used.
Suitable complexes are, for example, the following ruthenium complexes of optically active bisphosphines defined by the general formulas (III) to (X), without being restricted thereto:
Ru2Cl4B2(S)xe2x80x83xe2x80x83(III)
[Ru Hal Q B]+ Yxe2x88x92xe2x80x83xe2x80x83(IV)
Ru Bn OOCR10OOCR11xe2x80x83xe2x80x83(V)
[Ru Hx Bn]m+ Ymxe2x88x92xe2x80x83xe2x80x83(VI)
[Ru Hal (PR122R13)B](2+)Halxe2x88x922xe2x80x83xe2x80x83(VII)
[Ru H Hal B2]xe2x80x83xe2x80x83(VIII)
[B Ru (acac)2]xe2x80x83xe2x80x83(IX)
xe2x80x83[B Ru Y2]xe2x80x83xe2x80x83(X)
where
acac denotes acetylacetonate,
B represents a bisphosphine of the general formulas (B1) to (B15),
Hal represents halogen, in particular chlorine, bromine, or iodine,
R10 and R11 are identical or different and represent C1-C9-alkyl (preferably C1-C4-alkyl) which is optionally substituted by halogen (particularly fluorine, chlorine, or bromine), phenyl which is optionally substituted by C1-C4-alkyl, or an xcex1-aminoalkyl acid having preferably up to 4 carbon atoms, or R10 and R11 together form an alkylidene group having up to 4 carbon atoms,
R12 and R13 are identical or different and represent optionally substituted phenyl (preferably substituted by C1-C4-alkyl or halogen),
Y represents halogen, CIO4, BF4, or PF6,
Q represents an unsubstituted or substituted benzene ring, preferably p-cymene,
S represents a tertiary amine, preferably triethylamine, tri-n-butyl-amine, or pyridine,
n and m are identical or different and are 1 or 2, and
x represents 0 or 1,
with the proviso that in formula (VI) n represents 1 and m represents 2 when x is 0, and n represents 2 and m represents 1 when x is 1.
The complexes of the general formulae (III) to (IX) can be prepared by known methods.
The complexes of the formulae (III) and (VIII) may be prepared, for example, in a manner similar to that according to the processes described in EP-A 174,057 or in J. Chem Soc. Chem. Comm., 922 (1985).
The complexes of the general formula (IV) are given by, for example, reacting known ruthenium complexes [RuHal2Q]2 with bisphosphines of the general formula (B1) in inert organic solvents, for example as described in EP-A 366,390 or EP-A 749,973.
Complexes of the general formula (V) where n is 1 can be obtained, for example, by processes which are specified in EP-A 245,959, by reacting complexes of the general formula (Ill) with the corresponding carboxylic acids.
Complexes of the general formula (V) where n is 2 or n is 1 and R10 and R11 are CF3 can be prepared by processes specified in EP-A 272,787.
The complexes of the general formula (VI) can be prepared in a similar manner to the process according to EP-A 256,634.
The complexes of the general formula (VII) can be prepared in a similar manner to the process according to EP-A 470,756.
Complexes of the general formula (IX) can be prepared in a similar manner to the processes specified in Organometallics, 1993, 1467.
The complexes of formula (X) can be prepared in a similar manner to the processes specified in J. Am. Chem. Soc., 1987, 109, 5856-5858 or in Tetrahedron: Asymmetry, 5, 1994, 675-690.
Complexes based on rhodium or iridium can also be prepared by known methods by, for example, reacting, in a suitable, inert organic or aqueous solvent, the corresponding bisphosphine with a compound which can release rhodium or iridium.
Rhodium-releasing compounds that can be used, are, for example organic rhodium complexes with ethylene or propylene or with bisolefins such as 1,5-cyclooctadiene, 1,5-hexadiene, bicyclo[2,2,1]hepta-2,5-diene or with other dienes that readily form soluble complexes with rhodium. Preferred rhodium-releasing compounds are, for example, dichloro-bis-(1,5-cyclooctadiene)dirhodium, dichloro-bis(norbornadiene)dirhodium, bis-(1,5-cyclococtadiene)rhodium tetrafluoroborate, or bis(cyclooctadiene)rhodium perchlorate. An iridium-releasing compound which may be mentioned is, for example, dichloro-bis-(1,5-cyclooctadiene)diiridium.
When the inventive process is carried out, these catalyst complexes can be prepared first and, if appropriate, isolated and then added to a solution of the starting materials of the general formula (II). Alternatively, however, they can also be prepared in situ, that is to say already in the presence of the starting materials of the general formula (II).
In the preparation of the catalyst complexes, the ratio of metals to bisphosphines of the general formula (B1) to (B15) is expediently in the range 0.5 to 2 mol, preferably in the range 0.9 to 1.1 mol of ruthenium per mole of bisphosphine ligand. The ratio of metal in the complexes to the compounds of the formula (II) is customarily in the range 1:10 to 1:106, preferably in the range 1:30 to 1:105.
The enantioselective hydrogenation can be performed in a suitable organic solvent which is inert under the reaction conditions. Suitable solvents of this type, are, for example, lower alcohols having 1 to 6 carbon atoms, or mixtures of such alcohols with halogenated hydrocarbons, such as methylene chloride or chloroform, or with ethers or cyclic ethers such as diethyl ether, tetrahydrofuran, or dioxane, or with ketones such as acetone, methyl ethyl ketone, or methyl isobutyl ketone. Compounds that are also suitable as mixing partners are aliphatic hydrocarbons, such as hexane and heptane, cycloaliphatic hydrocarbons, such as cyclohexane and methylcyclohexane, or aromatic hydrocarbons, such as toluene and benzene. The mixing partners can, if appropriate, also be used in pure form.
Compounds of the general formula (II) are expediently enantioselectively hydrogenated in the presence of optically active bisphosphine catalysts at a temperature in the range 0 to 150xc2x0 C., preferably in the range 15 to 100xc2x0 C.
The pressure is in the range 1 to 250 bar hydrogen, preferably in the range 5 to 200 bar, and particular preference is given to a hydrogen pressure in the range 20 to 180 bar.
The inventive process is distinguished by a very good yield and a simultaneously high enantioselectivity. The use of cofactorxe2x80x94as in the case of the enzymatic reduction using an alcohol dehydrogenasexe2x80x94is not necessary. Also, the use of borane reagents which are expensive and complicated to synthesize is not necessary. It is surprising that the optically active bisphosphine ligands which are already known for other asymmetric hydrogenations also lead to an excellent enantioselectivity in the case of the trimethylpyruvic acid (esters) used here, which are highly demanding sterically. Enantiomeric excesses of 40% ee or more are achieved. Preferably, enantiomeric excesses xe2x89xa790% ee are achieved, and in particular xe2x89xa795% ee.